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Biomarkers in the cerebrospinal fluid of people newly diagnosed with Parkinson’s may tell physicians about the patient’s subtype of disease and risk of future cognitive decline. According to a report in the August 26 JAMA Neurology, this finding represents the first glimpse at CSF data from the Parkinson’s Progression Markers Initiative (PPMI), a large international effort that seeks to find tools to track the disease. Parkinson’s is a heterogeneous disease, where many patients stay stable for years while others decline rapidly. Physicians need a way to identify patients at the greatest risk of progression as early as possible. The researchers, led by Leslie Shaw at the University of Pennsylvania, Philadelphia, found that people with the rapid form of PD had less Aβ42, p-tau, and α-synuclein in their CSF.

Shaw and colleagues analyzed samples from the first 102 people who enrolled in PPMI. This pilot study found that people with the most rapidly progressing form of PD displayed a distinct CSF biomarker profile, suggesting that these markers could be used to stratify patients. This form of PD also carries the highest risk of dementia. It remains to be seen whether these preliminary findings will repeat in forthcoming analyses of the entire cohort, which includes imaging and genetic biomarkers as well. Nonetheless, the initial data support the hypothesis that CSF biomarkers will provide key pathophysiologic information that can help predict disease progression, Shaw told Alzforum. Shaw hopes that the systematic measurement of highly standardized biomarker tests in the PPMI study will provide the basis for their use in future treatment trials. The tests could help to assign risk for disease progression and monitor response to therapy.

Other researchers found this first look intriguing. “It sheds light on the complexity of these biomarkers. Early detection biomarkers are going to be crucial for the future of therapeutics for these diseases. We need more of these type of studies,” Amy Pooler at King’s College London, U.K., told Alzforum. She was not involved in the work.

PPMI is a five-year observational study modeled after the Alzheimer’s Disease Neuroimaging Initiative and conducted at 24 sites in the U.S., Europe, and Australia (see ARF related news story). Researchers completed enrollment of 400 PD and 200 controls earlier this year. For this study, Shaw and colleagues looked at baseline data from 63 PD patients and 39 age-matched controls. Most patients had received their diagnosis within the last five months before enrolling, and none had taken medication at the start of the study. The researchers compared CSF levels of α-synuclein, Aβ42, total tau, and tau phosphorylated at residue 181 (p-tau181), adjusting data to eliminate potential confounding effects from age, sex, and education. All methods were standardized to reduce variability from site to site, and an analysis showed little fluctuation between different runs of quality control samples, the authors report. They also controlled for possible contamination of blood into CSF, since blood cells contain large amounts of α-synuclein that can skew results.

The analysis revealed a distinct CSF biomarker profile for patients diagnosed with the postural instability-gait disturbance (PIGD) form of Parkinson’s, compared to those with the more common tremor-dominant (TD) PD. The 14 patients with PIGD had significantly lower Aβ42, p-tau, and α-synuclein than did the 43 TD patients, who were much closer to the profile of healthy controls. PIGD progresses more rapidly than other forms of Parkinson’s, and is associated with a greater risk of cognitive decline and dementia (see Burn et al., 2006; Alves et al., 2006). “PIGDs stand out in this study as having the greatest amount of pathology,” Shaw noted. The remaining six patients in this study had an intermediate phenotype, but their numbers were too small to draw conclusions about this group.

“This [PIGD] observation is consistent with our own observations in patients with early, drug-naïve PD, and we share the authors’ hope that these markers therefore could become promising and—importantly—very early prognostic markers of disease progression in PD,” Guido Alves at Stavanger University Hospital, Norway, wrote to Alzforum (see full comment below and Alves et al., 2013).

The pilot study found that in PD patients overall, all four biomarkers were significantly lower than in controls. However, this finding was mostly driven by the PIGD patients. Also, values overlapped a great deal among individual patients and controls, indicating that these four markers by themselves are not sensitive or specific enough to serve as a diagnostic of Parkinson’s, the authors point out.

The case for tau is more ambiguous. While some previous studies found tau to be low in PD (see, e.g., Zhang et al., 2008; Shi et al., 2011), others report high levels, particularly in PD patients with dementia (see Mollenhauer et al., 2006; Compta et al., 2009). Shaw saw variability of tau levels even within the PPMI study. “In the average PD patient, tau is low. But if you look at the entire range across this pilot study, there’s a small percentage of patients with highly elevated tau and p-tau,” he told Alzforum. It may be that high tau characterizes a subset of PD patients who have concomitant Alzheimer’s pathology and are at high risk of dementia, he suggested. Amyloid β pathology has been shown to amp up the risk of dementia in PD (see ARF related news story; see ARF related news story). This could also explain why the researchers found low Aβ42 in PD patients. This finding might be due to the subset of patients with AD pathology, Shaw speculated. It is unclear if the PD patients who had high tau also had low Aβ42, however.

Why might tau drop in most PD patients? Perhaps α-synuclein keeps tau out of the CSF, the authors suggest. In this study, tau and α-synuclein levels correlated with each other, not only in patients but also in healthy controls. Among PD patients, those with the worst movement problems had the lowest levels of tau and α-synuclein. Previous work has shown that α-synuclein can stimulate tau phosphorylation (see Jensen et al., 1999), and the two proteins can seed each other to form fibrils (see ARF related news story; ARF related news story). “We don’t know the mechanism yet, but animal model data suggests an interaction between these biomarkers that results in a lowering of the concentration, a sequestering of tau and p-tau for example by the presence of α-synuclein,” Shaw said.

To show sequestration, researchers would want to know whether CSF tau levels correlate with neurofibrillary tangles (NFTs) in the brain, Pooler said. Tau tracers now under development might make such a study possible (see ARF related news story). “Low tau is surprising, because we see an increase in tau in traumatic brain injury and AD,” Pooler told Alzforum. All three diseases are characterized by NFTs. Instead of sequestering tau in PD, α-synuclein might dampen physiological release of tau, Pooler speculated (see ARF related news story). This would suggest a different mechanism at work in Parkinson’s than in AD and traumatic brain injury, where high levels of tau are thought to reflect its release into the interstitial fluid upon neurodegeneration and cell death. Future work should characterize the form, aggregation state, and packaging of CSF tau in PD patients, Pooler suggested.

Shaw agrees more work is needed to parse the pathology of PD. “We believe very strongly that this data, because of the high level of standardization, is a great start point for developing meaningful hypotheses that we’ll be able to test during the next year or so,” he said.—Madolyn Bowman Rogers

This publication is interesting because it presents some of the first cerebrospinal fluid (CSF) biomarker findings from the Parkinson’s Progression Markers Initiative (PPMI) study, which many—including myself—consider a landmark study in PD. The PPMI is unique for several reasons, but in particular because it is specifically designed to identify biomarkers to predict and track disease progression in PD. This is a major unmet need the field.

In my view, the main finding is the observed association of lowered CSF biomarkers, Aβ1-42 and p-tau in particular, with the so-called postural instability–gait disturbance (PIGD) phenotype, which is known to signal a more rapid disease course in PD, both in terms of motor and cognitive decline. This is consistent with our own observations in patients with early, drug-naïve PD, and we share the authors’ hope that these markers could become promising and—importantly—very early prognostic markers of disease progression in PD. Although there are a few small longitudinal studies that provide some support for this view, we need to bear in mind that the data presented by Kang et al. are cross-sectional and include only the initial 102 subjects (63 with PD) of the PPMI cohort. Still, the PPMI has finished recruitment of more than 400 de novo PD patients earlier this year, and I assume that we can expect the first longitudinal results from this unique cohort in the near future.